Role of AP-2beta in Anterior Segment Development

 描述(申请人提供)：眼前段发育不全(ASD)是一种眼睛的发育异常，可累及多种组织，包括角膜、虹膜、晶状体、睫状体和眼部引流结构，包括小梁网(TM)和Schlemm管。因此，ASD与青光眼和角膜混浊的风险增加有关。事实上，50%的ASD患者会因为房水体液引流中断而出现青光眼，这会导致眼压升高。眼球前段结构的畸形被认为是由于眼周间充质(POM)分化和迁移的缺陷所致，POM是神经脊的衍生物。尽管不适当的POM模式与ASD密切相关，但ASD中POM功能和/或破坏的机制尚不清楚。我们的实验室已经证明，激活转录因子？(AP-2？)在出生后小鼠眼部的POM和POM来源的组织中高表达。此外，我们还发现，在POM(使用针对眼睛POM的WNT-1 CRE驱动程序)中有条件地删除Tfap2b(编码AP-2ç的基因)会导致完全穿透性闭角型青光眼表型，虹膜附着在角膜上。有趣的是，我们的初步发现还表明，Wnt-1Cre/AP-2？突变体表现出青光眼的特征，包括RGC丢失和视网膜神经胶质细胞反应性增加。在目前的方案中，我们将继续在小鼠身上使用条件性KO方法来确定AP-2ü基因在包括TM和角膜在内的前角组织的发育中所起的单独作用(S)。我们还将使用最先进的“组学”水平分析来确定前段正常基因表达的模式，以及它们是如何被Tfap2b丢失扰乱的。最后，我们将进一步评估在所建立的小鼠模型中观察到的青光眼变化，以进一步了解闭角型青光眼和视神经病变的病理生理学。

 DESCRIPTION (provided by applicant): Anterior segment dysgenesis (ASD) is a developmental anomaly of the eye that can involve multiple tissues including the cornea, iris, lens, ciliary body and ocular drainage structures including the trabecular meshwork (TM) and Schlemm's canal. As a result, ASD is associated with an increased risk of glaucoma and corneal opacities. In fact, glaucoma will arise in 50% of patients with ASD due to disruption in aqueous humour drainage, which leads to an elevation in intraocular pressure (IOP). Malformation of structures in the anterior segment of the eye is thought to occur due to a defect in the differentiation and migration of the periocular mesenchyme (POM), a derivative of neural crest. Although inappropriate patterning of the POM is strongly implicated in ASD, the mechanisms of POM function and/or disruption in ASD are unclear. Our laboratories have shown that activating transcription factor ß (AP-2ß) is highly expressed in the POM and POM-derived tissues of the post-natal mouse eye. Furthermore, we have found that conditional deletion of Tfap2b (the gene encoding AP-2ß) in the POM (using a Wnt-1 Cre driver that targets the POM of the eye) leads to a fully penetrant, angle closure glaucoma phenotype with the iris adhering to the cornea. Interestingly, our preliminary findings also show that the Wnt-1Cre/AP-2ß mutant's exhibit features of glaucoma including RGC loss and increased retinal glial reactivity. In the current proposal we will continue to utilize conditional KO approaches in mice to identify the individual role(s) that the AP-2ß gene plays in development of the anterior angle tissues including the TM and cornea. We will also use state-of-the-art "omics" level analyses to determine the patterns of normal gene expression in the anterior segment and how they are disrupted by loss of Tfap2b. Finally, we will further assess the glaucomatous changes observed in the mouse models generated to further understand the pathophysiology of closed angle glaucoma and optic neuropathy.